Editors' ChoiceGenetics

An integrative analysis sheds light on methylation profiles

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Science Translational Medicine  13 Jan 2016:
Vol. 8, Issue 321, pp. 321ec8
DOI: 10.1126/scitranslmed.aaf0857

DNA methylation is an important mechanism for controlling gene expression, and DNA methylation alterations are associated with many common diseases. In mammalian somatic cells, DNA methylation occurs almost exclusively at cytosine nucleotides of CpG sites, in which a cytosine is located next to a guanidine. DNA methylation varies with sex, age, exposure to environmental factors, and underlying genetic sequences. Genetic influence on DNA methylation tends to go unheeded, but it is potentially an important mechanism affecting individual differences in humans.

McClay et al. performed a high-density methylation quantitative trait loci (meQTL) analysis on 697 healthy human blood samples to test for genetic influence on DNA methylation patterns. The authors found that 15% of methylation sites showed genetic influence. This frequency is much higher than is usually observed in human disease studies. Most meQTLs were found at local single-nucleotide polymorphisms (SNPs), defined as those located within 1 Mb of the associated methylation sites, and the majority of local meQTLs contained SNPs that alter CpG sites (CpG-SNPs). The local meQTLs encompassing CpG-SNPs were enriched in regions of inactive chromatin in blood cells, suggesting that these meQTLs were less likely to have biological functions. In contrast, although most of the local meQTLs that overlapped disease-related SNPs were also CpG-SNPs, these were enriched in enhancers. These findings suggest that although many meQTLs lack functional consequences, a subset of meQTLs located in active chromatin regions could contribute to disease. Therefore, it will be important to integrate chromatin structure profiles and DNA methylation profiles to differentiate functional meQTLs from nonfunctional ones.

Because of the limitations of the method that the authors used, they were not able to pinpoint a specific CpG influenced by the genetic variations. However, their results clearly indicate that genetic influence is not negligible for testing DNA methylation profiles in human studies. In addition, integrating meQTL analysis with other epigenetic information such as chromatin structures will be important for functional interpretation of identified SNPs.

J. L. McClay et al., High density methylation QTL analysis in human blood via next-generation sequencing of the methylated genomic DNA fraction. Genome Biol. 10.1186/s13059-015-0842-7 (2015). [Full Text]

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